Anemia is characterized by a lower than normal number of red blood cells (erythrocytes) in the blood, usually measured by a decrease in the amount of hemoglobin. The cause of anemia can include chronic inflammation, chronic kidney disease, kidney dialysis treatment, genetic disorders, chronic infection, acute infection, cancer and cancer treatments. Altered iron homeostasis and/or erythropoiesis in these conditions can result in decreased erythrocyte (red blood cell) production. Anemia can limit the use of chemotherapeutic agents during cancer treatment. Symptoms of anemia include fatigue, pallor and poor exercise tolerance. Though rarely life threatening, anemia can be severely debilitating and difficult to treat. Clinical signs of anemia include low serum iron (hypoferremia), low hemoglobin levels, low hematocrit levels, decreased red blood cells, decreased reticulocytes, increased soluble transferrin receptor and iron restricted erythropoesis.
In some cases, increasing dietary iron or intravenous iron delivery are used to treat anemia. Erythropoietin (EPO) stimulates erythroprogenitors and promotes red blood cell formation. Recombinant erythropoietin and other erythropoiesis stimulating agents (ESAs) are used for treating anemia, although certain patients respond poorly to this treatment. EPO is well known and is commercially available through Amgen (Thousand Oaks, Calif.).
Anemia of chronic disease (ACD) is a highly prevalent, inflammatory-driven disorder that is poorly treated with currently available therapies. The mechanism underlying ACD is chronic inflammation, which results in changes in iron homeostasis and utilization, resulting in a blunting of erythroid progenitor cell proliferation and red cell function.
ACD is associated with increased production of inflammatory cytokines, including, for example, tumor necrosis factor-.alpha., IL-1.beta., IL-6, and interferon-.gamma. (Means (1995) Stem cells 13:32-37 and Means (1999) Int J Hematol 70:7-12). In several in vitro and in vivo animal model systems, inflammatory cytokines negatively affected the ability to mediate erythropoietin (EPO) production, EPO responsiveness, and the coordinate regulation of iron metabolism (Roodman et al. (1989) Adv Exp Med Biol 271:185-196; Fuchs et al. (1991) Eur J Hematol 46:65-70; Jelkmann et al. (1994) Ann NY Acad Sci 718:300-311; Vannucchi et al. (1994) Br J Hematol 87:18-23; and Oldenburg et al. (2001) Aliment Pharmacol Ther 15:429-438). Administration of EPO failed to reverse anemia in mice continuously exposed to TNF-.alpha. (Clibon et al. (1990) Exp Hematol 18:438-441). Increased levels of inflammatory cytokines, such as TNF-.alpha., IL-1.beta., and INF-.gamma., contribute to defective EPO production and EPO resistance observed in patients with anemia of chronic disease (Jelkmann et al. (1991) Ann NY Acad Sci 718:300-311 and Macdougall and Cooper (2002) Neprol Dial Transplant 17(11):39-43.). Therefore, various cytokines, e.g., inflammatory cytokines and cytokines associated with inflammation, are involved in many aspects of the pathogenesis of anemia of chronic disease, including inhibition of erythroid progenitors, inhibition of EPO production, and impairment of iron release and iron availability for erythropoiesis.
Hepcidin is an 8 kD polypeptide that is produced by hepatocytes in response to inflammation or to rising levels of iron in the blood. The primary role of hepcidin is to regulate blood iron levels by facilitating a decrease in these blood iron levels. Hepcidin binds with and down regulates ferroportin to reduce ferroportin mediated release of iron into the blood. Hepcidin expression is increased in conditions of acute and chronic inflammation resulting in decreased iron availability for erythropoeisis. Hepcidin is frequently measured in the urine or serum as a biomarker of anemia status. (Ganz et al. (2006) Am J Physiol Gastrointest Liver Physiol 290:G199-G203; and Ganz (2003) Blood 102(3):783-788). Moreover, hepcidin over expression has been strongly linked to ACD mechanistically as a mediator of this disorder in animal models and in humans.